The overall objective of this project is to determine the mechanism of cocaine-induced immunosuppression and to further characterize the combined effects of cocaine with morphine and stress on the immune system. Specifically, the experiments described in this proposal will first test the hypothesis that the in vivo suppression of lymphocyte proliferative responses by single doses of cocaine: 1. is mediated through the activation of central dopaminergic neurons 2. requires the stimulation of the hypothalamic-pituitary-adrenal axis 3. requires the stimulation of the autonomic nervous system. Secondly, it is hypothesized that multiple doses of cocaine, which produces either tolerant or sensitized states, will result in an increased sensitivity to the immunosuppressive effects upon re-exposure to cocaine, co-treatment with morphine or exposure to a stressor. The specific aims which will address these hypotheses include: AIM #1: To identify the central site(s) which are involved in the mediation of cocaine-induced inhibition of peripheral immune cell activity. These studies will determine the time- and dose-dependency of the effects of bilateral injections of cocaine in the dopaminergic neurons and terminals of the substantia nigra, striatum, ventral tegmental area, nucleus accumbens, amygdala and the prefrontal cortex. AIM #2: To pharmacologically characterize the central monoaminergic systems involved in the immunosuppressive effects of cocaine. At selected central sites, the studies proposed will first examine whether the effects of cocaine on the immune system are related to the inhibition of dopamine uptake, a neurochemical change which is related to the reinforcing effects of cocaine. AIM #3: To examine the possible peripheral mechanisms by which activation of central pathways by cocaine result in suppressed lymphocyte activity. These studies will determine whether immunosuppression following acute cocaine administration may be mediated peripherally through its well-known effects on both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. In addition, studies will continue to characterize a serum factor produced by cocaine-treated animals which reproduces the immunosuppressive effects of cocaine in drug-naive rats. AIM #4: To determine whether cocaine 'tolerant' or 'sensitized' animals have an increased susceptibility to the immunosuppressive effects of either morphine or stress. By altering the dosing schedule to repetitive cocaine administration, animals will be made either tolerant or sensitized to re-exposure to the drug. Little is known how either of these states affect the immune system or the further impact of subsequent exposure to either morphine or stress. The underlying assumption is that this paradigm most closely represents the pattern of cocaine abuse by humans. Given the almost epidemic proportions of cocaine abuse and HIV infections, more information of the effects of cocaine on the immune system is necessary to ultimately evaluate whether these effects contribute to a higher susceptibility to HIV infection.